Overview: Although there is consensus that HIV accelerates hepatitis C (HCV) disease in co-infected (HIV+HCV+) patients, studies differ regarding the impact of HCV infection on HIV disease progression. This proposal seeks continued support for our grant HCV and Progression of HIV and HAART Response in Women . During the past 5 years we found that HCV accelerates HIV disease progression and that this is related to immune activation and altered T cell maturation as a result of dual viral infection. Our central hypothesis is that HIV disease progression is impacted by enhanced CD8 activation and altered T cell maturation as a result of HCV viral dynamics and that HAART will not completely reverse this in the setting of ongoing HCV replication. Specific Aims: 1) Determine the relationships among extrahepatic replication of HCV in PBMC, HCV dynamics and HIV disease progression in co-infected HCV viremic women. 2) Longitudinally investigate the relationship of T cell activation/maturation and function and a) HCV quasispecies dynamics and extrahepatic reservoirs. b) Disease progression. 3) Assess the relationship of HCV reservoirs in PBMC and HCV quasispecies dynamics with HIV viral load response (VLR) and rebound post-HAART. 4) Determine the relationship of immune activation and T cell maturation/function with HIV VLR and rebound post-HAART and correlate with extrahepatic replication and quasispecies diversity. Clinical Significance: Our studies thus far find that compared with singly infected women, co-infected women had: a) an almost two-fold increased probability of developing AIDS among women who never had CD4 counts <200 cells/mm3;b) an increased relative hazard (RH) of AIDS and death at lower HIV RNA levels;c) increased RH of AIDS associated with higher levels of activated CD8+ T cells;they also had d) a 40% prevalence of HCV replication in PBMC which was associated with alcohol use and prior AIDS;and, e) a 3 fold increase in changes in HCV quasispecies among active IDU. These findings support our hypothesis that HCV dynamics contributes to immune dysregulation and the development of AIDS and AIDS-related death. Co- infected women may need to initiate antiretroviral treatment (ART) at lower HIV RNA and higher CD4 count thresholds than is currently recommended, to prevent AIDS/death. Given the many clinical, demographic and behavioral characteristics associated with HIV disease progression, a large cohort is needed. The proposed study will allow us to better define those who may benefit from more aggressive ART.In this study we will determine the relationships among extrahepatic HCV replication in PBMC, HCV dynamics and a) HIV disease progression;b) long-term response to HAART among HIV infected and HIV and HCV co- infected women from the Women's Interagency HIV Study. Further, we will longitudinally investigate the relationship of T cell activation/maturation and function with a) HCV quasispecies dynamics and extrahepatic reservoirs and b) HIV disease progression.